ISDA: 9WHC

Deposition Date 2025-08-26

Release Date 2026-07-08

Last Version Date 2026-07-08

Entry Detail

PDB ID:

9WHC

Keywords:

OXIDOREDUCTASE

Title:

Crystal structure of human nNOS PDZ domain in complex with compound N28

Biological Source:

Source Organism(s):

Homo sapiens (Taxon ID: 9606)

Expression System(s):

Escherichia coli

Method Details:

Experimental Method:

X-RAY DIFFRACTION

Resolution:

2.80 Å

R-Value Free:

0.28

R-Value Work:

0.24

R-Value Observed:

0.24

Space Group:

C 1 2 1

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Macromolecular Entities

Structures with similar UniProt ID

Structural Superimposition Protein Blast

Polymer Type:polypeptide(L)
Molecule:Nitric oxide synthase 1
Gene (Uniprot):NOS1
Chain IDs:A, B, C
Chain Length:126
Number of Molecules:3
Biological Source:Homo sapiens

UniProt ID:P29475 Pfam ID:PF00595 EC:1.14.13.39

Ligand Molecules

A1EWG

Primary Citation

Identification of a Potent and Selective Small-Molecule Inhibitor Targeting the nNOS-PDZ Domain that Exhibits Rapid In Vivo Antidepressant Efficacy.

Zhang, L, Xiong, Z, Chen, S, Zhu, Q, Wang, Y, Lu, Q, Bu, X, Xia, A, Chen, L, Chen, C, Shao, Z, Li, L, Yang, S.Show

J.Med.Chem. 69 14513 14529 (2026)

PMID: 42234972 DOI: 10.1021/acs.jmedchem.6c00391

Abstact

The PDZ domain of neuronal nitric oxide synthase (nNOS-PDZ) plays a crucial role in regulating serotonin signaling in the forebrain and has emerged as a promising target for developing rapid-acting antidepressants. Here, we report the identification of N24, a potent and selective small-molecule inhibitor of nNOS-PDZ. N24 induces a substantial thermal shift (DeltaT(m)) of 5.44 degrees C in a differential scanning fluorimetry (DSF) assay and displays an IC(50) of 0.76 +/- 0.07 muM in a fluorescence polarization (FP) assay. The cocrystal structure of the nNOS-PDZ-N24 complex reveals key binding interactions. In vivo, N24 produces rapid, dose-dependent antidepressant effects in mouse models of depression induced by chronic unpredictable mild stress (CUMS) and chronic corticosterone treatment, with no evidence of addictive potential or motility-related side effects. Together, these results establish N24 as a potent and selective nNOS-PDZ inhibitor, providing a promising lead compound for the development of antidepressants.

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Primary Citation of related structures

Abstact

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